Normative modeling for quantitative brain MRI phenotyping and biomarker discovery for pediatric leukodystrophies

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Abstract

ImportanceLeukodystrophies are a heterogeneous group of genetic disorders affecting the white matter of the brain, often presenting with overlapping clinical features but differing in neuroanatomical involvement. There is a critical need for quantitative tools to characterize disease burden and support diagnosis, severity stratification, and clinical trial readiness. ObjectiveTo characterize shared and distinct neuroanatomical patterns across six genetically confirmed leukodystrophies using anatomical MRI-derived phenotypes benchmarked against brain growth charts, and to assess the utility of this methodological approach for identifying imaging biomarkers of disease severity. DesignCross-sectional neuroimaging study using retrospective clinical MRI data. SettingMulticenter study incorporating data from the Global Leukodystrophy Initiative Clinical Trials Network (GLIA-CTN) and control data from the Childrens Hospital of Philadelphia. ParticipantsThe study included 434 MRI scan sessions from 274 patients with genetically confirmed leukodystrophies (Pelizaeus-Merzbacher disease, Metachromatic leukodystrophy, Alexander disease, Aicardi-Goutieres syndrome, TUBB4A-related leukodystrophies, and POLR3-related leukodystrophy). Control MRI data (7628 scans from 7205 subjects) were drawn from the Scans with Limited Imaging Pathology cohort at the Childrens Hospital of Philadelphia. ExposuresAll MRI scans underwent automated segmentation using deep learning segmentation tools to derive global and regional brain volumes. Normative models of brain development ("brain growth charts") were generated for the control cohort using generalized additive models for location, scale, and shape. Centile scores were then calculated for leukodystrophy subjects to quantify deviations from typical development. Main Outcomes and MeasuresCentile scores for global and regional brain volumes were compared across leukodystrophy subtypes to identify disease-specific neuroanatomical patterns and to evaluate their potential utility for severity stratification. ResultsDistinct patterns of neuroanatomical deviation were observed across leukodystrophy subtypes. Certain leukodystrophies showed preferential involvement of specific cortical or subcortical regions, while others displayed more diffuse volume loss. Centile scores demonstrated potential for differentiating disease subtypes and stratifying individuals by severity. Preliminary longitudinal data suggest centile scores may also track progression over time. Conclusions and RelevanceThis study demonstrates the feasibility and utility of MRI profiling of individuals with leukodystrophy using anatomical MRI-derived phenotypes benchmarked against brain growth charts. The approach enables data-driven, quantitative characterization of structural brain abnormalities, offering a scalable method for phenotyping, diagnosis, and future use in clinical trials. Key PointsO_ST_ABSQuestionC_ST_ABSIn genetically confirmed leukodystrophies, can anatomical MRI measurements benchmarked against brain growth charts identify neuroanatomical patterns that correlate with clinical function and disease severity? FindingsIn this cross-sectional neuroimaging study of six leukodystrophies, imaging-derived quantitative phenotypes benchmarked against brain growth charts revealed neuroanatomical patterns of volume loss consistent with previously-reported qualitative changes for each disorder. These patterns of regional volume loss correlated with measures of clinical function, particularly in POLR3-related leukodystrophy, TUBB4A-related leukodystrophy, and Aicardi-Goutieres Syndrome. MeaningBrain growth charts may be a valuable tool for characterizing the patterns of involvement across different leukodystrophies. Furthermore, this approach may facilitate the use of atrophy as a biomarker for assessing disease severity in clinical trials.

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